Docetaxel and epirubicin compared with docetaxel and prednisone in advanced castrate-resistant prostate cancer: a randomised phase II study.

BACKGROUND: This randomised phase II study compared the activity and safety of the combination docetaxel (D)/epirubicin (EPI) with the conventional treatment D/prednisone (P) in advanced castrate-resistant prostate cancer (CRPC) patients. MATERIALS AND METHODS: Patients were randomly assigned to D 30 mg m(-2) as intravenous infusion (i.v.) and EPI 30 mg m(-2) i.v. every week (D/EPI arm), or D 70 mg m(-2) i.v. every 3 weeks and oral P 5 mg twice daily (D/P arm). Chemotherapy was administered until disease progression or unacceptable toxicity. RESULTS: A total of 72 patients were enrolled in the study and randomly assigned to treatment: 37 to D/EPI and 35 to D/P. The median progression-free survival (PFS) was 11.1 months (95% CI 9.2-12.6 months) in the D/EPI arm and 7.7 months (95% CI 5.7-9.4 months) in the D/P arm (P=0.0002). The median survival was 27.3 months (95% CI 22.1-30.8 months) in the D/EPI arm and 19.8 months (95% CI 14.4-24.8 months) in the D/P arm (P=0.003). Both regimens were generally well tolerated. CONCLUSION: The treatment of advanced CRPC with weekly D combined with weekly EPI was feasible and tolerable, and led to superior PFS than the treatment with 3-weekly D and oral P.

Acute administration of 3,4-methylenedioxymethamphetamine (MDMA) induces oxidative stress, lipoperoxidation and TNFα-mediated apoptosis in rat liver.

Liver toxicity is one of the consequences of ecstasy (3,4-methylenedioxymethamphetamine MDMA) abuse and hepatocellular damage is reported after MDMA consumption. Various factors probably play a role in ecstasy-induced hepatotoxicity, namely its metabolism, the increased efflux of neurotransmitters, the oxidation of biogenic amines, and hyperthermia. MDMA undergoes extensive hepatic metabolism that involves the production of reactive metabolites which form adducts with intracellular nucleophilic sites. MDMA-induced-TNF-α can promote multiple mechanisms to initiate apoptosis in hepatocytes, activation of pro-apoptotic (BID, SMAC/DIABLO) and inhibition of anti-apoptotic (NF-κB, Bcl-2) proteins. The aim of the present study was to obtain evidence for the oxidative stress mechanism and apoptosis involved in ecstasy-induced hepatotoxicity in rat liver after a single 20 mg/kg, i.p. MDMA administration. Reduced and oxidized glutathione (GSH and GSSG), ascorbic acid (AA), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and malondialdehyde (MDA), an indicator of lipid peroxidation, were determined in rat liver after 3 and 6h after MDMA treatment. The effect of a single MDMA treatment included decrease of GR and GPx activities (29% and 25%, respectively) and GSH/GSSG ratio (32%) with an increase of MDA (119%) after 3h from ecstasy administration compared to control rats. Liver cytosolic level of AA was increased (32%) after 6 h MDMA treatment. Our results demonstrate a strong positive reaction for TNFα (p<0.001) in hepatocytes and a diffuse apoptotic process in the liver specimens (p<0.001). There was correlation between immunohistochemical results and Western blotting which were quantitatively measured by densitometry, confirming the strong positivity for TNF-α (p<0.001) and NF-κB (p<0.001); weak and intense positivity reactions was confirmed for Bcl-2, SMAC/DIABLO (p<0.001) and BID reactions (p<0.001). The results obtained in the present study suggest that MDMA induces loss of GSH homeostasis, decreases antioxidant enzyme activities, and lipoperoxidation that causes an oxidative stress that accompaines the MDMA-induced apoptosis in liver cells.

Chemotherapy-induced myelosuppression by vinorelbine: a comparison between different dose schedules by simulation.

A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to simulate the plasma profile and the toxicity of vinorelbine after multiple oral dose treatment to humans. The PK drug profile was described by a three-compartment open model linked to a PD model aimed to describe the drug toxicity on the circulating neutrophils. Different dose schedules were simulated holding the total administered dose constant (100 mg p.o. during two weeks): 7.7 mg daily (13 doses), 20 mg every 3 days (5 doses) and 33.3 mg every 6 days (3 doses). The lowest values of the circulating neutrophils were observed after 18 days from the start of the treatment and at nadir the fraction of the circulating neutrophils were 0.733, 0.703 and 0.681 after the three doses in decreasing order. These differences were not clinically significant, however the drug bioavailability, which was fixed to 0.35 in the simulation, might be highly variable among subjects contributing to a large extent to the observed variability in drug toxicity.

Passage of mannitol into the brain around gliomas: a potential cause of rebound phenomenon. A study on 21 patients.

AIM: Widespread use of mannitol to reduce brain edema and lower elevated ICP in brain tumor patients continues to be afflicted by the so-called rebound phenomenon. Leakage of mannitol into the brain parenchyma through an altered BBB and secondary reversal of osmotic gradient is considered the major cause of rebound . This has only been demonstrated experimentally in animals. As a contribution to this issue we decided to research the possible passage of mannitol into the brain after administration to 21 brain tumor patients. METHODS: Mannitol (18% solution; 1 g/kg) was administered as a bolus to patients (ten had malignant glioma, seven brain metastases and four meningioma) about 30 minutes before craniotomy. During resection, a sample of the surrounding edematous white matter was taken at the same time as a 10 ml venous blood sample. Mannitol concentrations were measured in plasma and white matter by a modified version of the enzyme assay of Blonquist et al. RESULTS: In most glioma patients, mannitol concentrations in white matter were 2 to 6 times higher than in plasma (mean 3.5 times). In meningioma and metastases patients plasma concentrations of mannitol were higher than white matter concentrations except in three cases with infiltration by neoplastic cells. CONCLUSIONS: The results of our study show that even after a single bolus, mannitol may leak through the altered BBB near gliomas, reversing the initial plasma-to-blood osmotic gradient, aggravating peritumoral edema and promoting rebound of ICP.

Evaluation of enzymatic and non-enzymatic antioxidants in seminal plasma of men with genitourinary infections, varicocele and idiopathic infertility.

UNLABELLED: This study was aimed to assess the antioxidant enzymatic and non-enzymatic compounds in semen of infertile men. Seventy-four infertile patients were grouped according to their clinical diagnosis: genitourinary infection, varicocele, idiopathic infertility. Semen samples of fertile men represent the control. Semen characteristics were evaluated by light and transmission electron microscopy (TEM). TEM data was quantified with a mathematical formula, which provides numerical scores. Spectrophotometric and HPLC methods were used to measure the amount of reduced (GSH), oxidised glutathione (GSSG), ascorbic acid (AA) and malondialdehyde (MDA, marker of lipid peroxidation) and the activity of glutathione reductase, catalase (CAT), glutathione peroxidase. Infertile groups showed significantly decreased values of sperm parameters vs. CONTROLS: In infection and varicocele groups, the seminal MDA levels were significantly increased when compared to controls (p < 0.001), indicating an alteration of oxidative status and a peroxidative damage. In infection and varicocele groups, AA levels were reduced (p < 0.05) vs. control; in the varicocele group, the GSH levels were also decreased (p < 0.05). Significantly higher CAT activity was observed in infection and varicocele groups vs. fertile men (p < 0.001 and p < 0.05 respectively). The GSH/GSSG ratio was significantly decreased in varicocele and idiopathic infertility groups vs. control (p < 0.01). The study of the alteration of a single parameter of oxidative stress or of the antioxidant system may not have a relevant clinical value to estimate male fertilising potential and the background of infertility causes, since complex and multifactorial mechanisms are involved in different pathologies. In our study, each pathology is characterised by a definite pattern of markers such as MDA and enzymatic and non-enzymatic antioxidant compounds. In the different pathologies related to infertility, the identification of the complex of involved parameters could be useful in the diagnosis, prognosis and in the choice of a possible treatment such as specific antioxidant supplements.

Glutathione, ascorbic acid and antioxidant enzymes in the tumor tissue and blood of patients with oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma is one of the most common cancers in the world. Reactive oxygen species are postulated to be involved in neoplastic transformation. The antioxidant defence system limits cell injury induced by reactive oxygen species. Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species and a cell's oxidant capacity or when there is a decrease in this capacity. This stress may cause mutagenesis, cytotoxicity and changes in gene expression that initiate or promote carcinogenesis. OBJECTIVES: The present study was conducted to investigate whether tumor tissue and blood of patients with oral squamous cell carcinoma have altered antioxidants levels. METHODS: Levels of antioxidants such as reduced glutathione (GSH) and ascorbic acid (AA) and the activities of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutatione reductase (GR), were estimated in the tumor tissue and blood of 18 oral squamous cell carcinoma patients and in 20 healthy subjects as control. RESULTS: Significantly increased levels of GSH, GPx, GR and AA and significantly decreased activity of SOD were observed in tumor tissue (p < 0.001) and in tumor-free tissue of oral cancer patients as compared with healthy subjects. In contrast, decrease in antioxidants (GSH, GPx, GR and AA p < 0.001, SOD p < 0.05 respectively) was observed in the blood of oral cancer patients, as compared with healthy subjects. CONCLUSION: The low levels of antioxidants in the blood of oral cancer patients may be due to their increased utilization to scavenge lipid peroxides as well as their sequestration by tumor cells. The enhanced antioxidant capacities in tumor tissues can make them less susceptible to oxidative stress, conferring a selective growth advantage on tumor cells. These finding suggest that normalization of the levels of these antioxidants might be used to reduce oral tumor malignancy.

Rechallenge of docetaxel combined with epirubicin given on a weekly schedule in advanced castration-resistant prostate cancer patients previously exposed to docetaxel and abiraterone acetate: a single-institution experience.

The aim of this paper was to evaluate the activity and tolerability of weekly docetaxel (D) combined with weekly epirubicin (EPI) in patients with advanced castrate-resistant prostate cancer (CRPC) previously exposed to D and abiraterone acetate (AA). Locally advanced or metastatic CRPC patients with 0-2 performance status, who had progressed after D and AA therapy, were included in the study. Previous treatment with chemotherapy agent cabazitaxel was also admitted. Treatment consisted of D 30 mg/m(2) intravenously (i.v.) and EPI 30 mg/m(2) i.v., every week (D/EPI). Chemotherapy was administered until disease progression or unacceptable toxicity. In our institution, twenty-six patients received D/EPI: their median age was 72 years (range 59-83 years). Twenty-three (88.5%) patients had bone metastases. A decrease in PSA levels ≥50% was observed in seven patients (26.9%, 95% CI: 0.11-0.47); of these, five had achieved a ≥50% PSA response during prior first-line D and six had achieved a PSA response during prior AA Among the subjects who were symptomatic at baseline, pain was reduced in nine patients (38.1%) with a significant decrease in analgesic use. Median progression-free survival was 4.4 months (95% CI, 3-5.2), and median overall survival was 10.7 months (95% CI, 8.9-18.4). Treatment was well tolerated and no grade 4 toxicities were observed. Our findings suggest that weekly D/EPI is feasible and active in heavily pretreated advanced CRPC patients and seem to support the hypothesis that the addition of EPI to D may lead to overcome the resistance to D in a subgroup of patients.

Acetazolamide-like carbonic anhydrase inhibitors with topical ocular hypotensive activity.

New carbonic anhydrase (EC 4.2.1.1) inhibitors were synthesized as potential drugs for the topical treatment of glaucoma. They were obtained by substituting the acetyl group of acetazolamide and methazolamide with bicarboxylic acids of different chain length (C4-C6). The terminal carboxyl was either kept free or esterified with alcohols of different size (C1-C12). A gamma-aminovaleric derivative was also prepared. All compounds proved active as carbonic anhydrase inhibitors in vitro, with an average IC50 of about 0.5 microM. Some proved also to be topically active in vivo in lowering the artificially elevated intraocular pressure in rabbits. The most active compound, carrying a succinic acid side chain, is the most soluble in aqueous buffers. Its duration of action is about 8 h and it is under evaluation as a topical antiglaucoma drug. It is hypothesized that the duration of action could be longer in compounds having both the same high water solubility and partition coefficient.

Effect of acetaminophen on glutathione levels in rat testis and lung.

Glutathione (GSH) levels in rat testis and lung after oral administration (3 g/kg) of acetaminophen (APAP) were studied. At the administered dose APAP is present in each organ and influences the GSH levels. APAP value of 114 micrograms/g was obtained in testis at 6 hr (peak time); in the lung the Cmax was 92 mu/g at 8 hr and this value lasted several hours longer than that in testis. GSH levels are also affected differently in the organs studied after APAP administration; the lungs seem to be the primary organ undergoing the depleting action of APAP. This process could not only cause toxicity, but also predispose those organs to the action of toxic compounds responsible for specific pathologies.

New 1,2,4-oxadiazole derivatives: synthesis and adrenergic receptors binding studies.

In order to obtain derivatives with simultaneous alpha- and beta-adrenergic blocking activity, compounds having the phenoxypropanolaminic structure of beta-adrenergic blockers have been synthesised, as well as 1,2,4-oxadiazole moiety, which could imitate the imidazolinic nucleus characteristic of drugs acting on alpha-adrenergic receptors. The synthesised compounds have been submitted to alpha and beta receptor binding assays. Some derivatives showed an alpha-adrenoceptor binding activity higher than labetalol and similar to prazosin, but with a poor beta-adrenoceptor binding activity.

New quinoline derivatives: synthesis and evaluation for antiinflammatory and analgesic properties--Note I.

New 4-anilinoquinoline-3-carboxylic acids, N-[3-carboxyquinolyl (4)]anthranilic acids and their corresponding esters were synthetized by reacting 4-chloro-3-carbethoxyquinolines with substituted anilines and methyl anthranilate respectively. All the compounds were tested for antiinflammatory and analgesic activities. Some derivatives showed a significant antiinflammatory activity comparable to that of indomethacin.

Non-steroidal anti-inflammatory drugs (NSAIDs) affect the glutathione (GSH) levels in the brain.

The authors in a previous research verified the effect of administration of three non steroidal antiinflammatory drugs (piroxicam, naproxen, ketoprofen) on the glutathione levels in various organs of rat. On the basis of these researches, the authors study the effect of the same anti-inflammatory drugs on glutathione levels in rat brain, dissected in order to analyze separately the cortex, cerebellum and the remaining part of the brain. The obtained results show that the distribution of the three drugs is not homogeneous in the studied areas and that these three drugs act differently on glutathione levels. These facts let us suppose that piroxicam, naproxen and ketoprofen produce toxic events that are different according to the brain areas we studied.

Plasma kinetics of atropine and ipratropium in rats after different routes of administration evaluated by a radioreceptor assay.

Plasma kinetics of atropine and ipratropium was assessed in rat after i.v. (10 mg/kg), oral and i.p. (50 mg/kg) administration by a radioreceptor assay (RRA). The volume of the central compartment and the clearance of both drugs were very similar (about 3 L/kg and 3.5 L/h/kg respectively) while the steady state volume of distribution and the terminal half-life of atropine were higher than those of ipratropium. After i.p. administration the kinetics of ipratropium was very different from what was expected after the i.v. experiment.

Blood profiles, body fat and mood state in healthy subjects on different diets supplemented with Omega-3 polyunsaturated fatty acids.

BACKGROUND: Diets and Omega-3 polyunsaturated fatty acids have been considered as important factors to reduce the risk of cardiovascular and inflammatory diseases, but there are few details on the effects on healthy subjects. The aim of the present study was to examine the variation of several physiological parameters in healthy subjects on different diets supplemented with Omega-3 fatty acids. MATERIALS AND METHODS: The experiment was carried out on 33 subjects divided into four groups according to a double-blind cross-over design with a 1 : 1 ratio for Omega-3 (vs. placebo) and open-label parallel-groups with a 1 : 1 ratio for the Zone diet (vs. the diet suggested by the Italian National Research Institute for Nutrition and Foods). Blood samples were collected at the beginning of the experiment and after 35 (cross-over) and 70 days. The Profile of Mood States test (POMS) was also performed. RESULTS: The arachidonic acid/eicosapentaenoic acid ratio (AA/EPA) was strongly reduced by Omega-3 with a supplementary effect of the diet and in particular the Zone diet. The AA/EPA reduction was correlated with a concomitant decrease of insulin and homocysteine levels. The Zone diet reduced skinfold thickness and body fat percentage and also showed antioxidant effects. The mood state changed after Omega-3 supplementation, with an increased POMS index. This was related to a concomitant reduction of AA/EPA and was particularly evident in the Zone diet. CONCLUSION: AA/EPA and mood state are differently influenced by diet and Omega-3, body fat is particularly reduced by Zone diet, while blood parameters such as triglycerides/HDL ratio, insulin and homocysteine are related to AA/EPA variations. These findings are discussed in terms of differences in the composition of the diets and the influences of Omega-3 on physiological functions.

Rapid and sensitive determination of piroxicam in rat plasma, muscle and skin by high-performance liquid chromatography.

A rapid and precise high-performance liquid chromatographic method for the determination of piroxicam in a variety of biological samples has been developed. A reversed-phase column, isocratic elution and ultraviolet detection were employed. Calibration curves were reproducible and highly linear, with correlation coefficients typically averaging over 0.992. The detection limit of the assay was 100 ng/ml for all biological samples examined (at a signal-to-noise ratio of 3:1). Validation of the method demonstrated a good sensitivity, accuracy and precision. The method has been adopted for a pharmacokinetic study in rats.

Effect of non-steroidal anti-inflammatory drugs on glutathione levels in various organs of rat.

Since glutathione (GSH) depletion (about 20% of total GSH content) can impair the cell's defence against the toxic actions of drugs and may lead to cell injury and death, we examined the effect of piroxicam, naproxen and ketoprofen on GSH levels in various organs of the rat (brain, eye, liver, stomach, heart, leg adductor muscle). Ketoprofen in brain and leg adductor muscle dramatically decreases the GSH levels, giving rise to potential cellular toxicity.

High-performance liquid chromatography of flufenamic acid in rat plasma.

A simple high-performance liquid chromatographic (HPLC) method for the determination of flufenamic acid in rat plasma is described. After liquid-liquid extraction, the drug is separated by HPLC on a 5-microns octadecylsilica column (Nucleosil C18) with ultraviolet detection at 280 nm. Linear calibration graphs for flufenamic acid were constructed from 0.5 to 15 micrograms/ml. The method has been applied to a pharmacokinetic study in animals.

Serum and urine kinetics of rosaprostol in volunteers.

The kinetics of rosaprostol (9-hydroxy-19,20-bis-norprostanoic acid, Rosal) and of its metabolite (3-(2-n-hexyl-5-hydroxy-cyclopentyl)propionic acid) has been determined in plasma and in urine of 10 healthy volunteers after oral administration of 500 mg of rosaprostol. The peak of rosaprostol (of 524 ng/ml) appears at 4 h, whereas that of the metabolite (of 503 ng/ml) appears earlier (2 h); therefore the relationship between the two substances does not follow the precursor-successor relationship in plasma and a compartmental model has been used to fit the data. In this model the biotransformation process occurs before entering the central compartment (first-pass effect). The mean half-life of rosaprostol is equal to about 5 h and that of the metabolite is equal to 3 h. All of rosaprostol is biotransformed and only the metabolite is partially eliminated by the urine. The urinary excretion of the metabolite represents only a small fraction of the administered dose. The urinary clearance of the metabolite is equal to 5.3 l/h. The volume of distribution of both substances is equal to 21.2 l.

Effect of buspirone on glutathione hepatic levels in rat.

The effect of oral administration of buspirone (0.5-1.0 and 2.0 mg/Kg) on GSH levels was studied in rat liver. The modulating activity of buspirone on hepatic content of this tripeptide is clearly opposite to that of DAZ, put into evidence by us in previous works. Thus our observations let us hypothesize a different mechanism of action for buspirone than that for benzodiazepines.

Inhibition of ornithine-decarboxylase produced by S(+) and R(-) ibuprofen in rats.

The differences between the S(+) and R(-) ibuprofen enantiomers in anti-inflammatory activity were assayed by measuring the release of 14CO2 in rats treated with labelled 14COOH-ornithine. Furthermore we investigated in vitro the inhibitory activity on ornithine-decarboxylase and the anti-inflammatory activity of R(-) and S(+) ibuprofen by using the carrageenin-induced paw oedema test in the rat.